tbuckley/cabot-search huggingface dataset:
Use of CLIA accredited multi-omic platforms to correlate clinical significance of WES/WTS testing with functional protein/phosphoprotein drug target activity.
Authors: Rachel Elsey, Tobias Meissner, Claudius Mueller, Brian Corgiat, Justin B Davis, Crystal Hattum, William Charles Spanos, David Starks, Benjamin Maurice Solomon, Emanuel Petricoin, John H. Lee, Casey B. Williams
Journal: Journal of Clinical Oncology (2023)

e15150 Background: Targeted cancer therapies almost exclusively disrupt protein function and phosphorylation, but genomics-based biomarkers underpin the vast majority of oncology molecular profiling. The reverse phase protein array (RPPA) technology has been used in the clinical setting to identify potential drug targets and to monitor the effects of treatment on protein expression and phosphorylation. Here, we investigated the Theralink RPPA assay, a highly sensitive CAP/CLIA accredited protein/phosphoprotein profiling technology, across a pan-tumor cohort of 188 samples which had undergone whole exome sequencing and transcriptomics. Methods: Using the Theralink RPPA assay, 32 key protein and phosphoprotein cancer therapy targets were quantified from formalin-fixed, laser capture microdissected (LCM) tumor epithelium across a pan-tumor cohort of 188 cancer cases. All samples had concomitant CLIA-based whole exome and whole transcriptome analysis performed. Most of these tumors were head and neck cancer (34%), uterine cancer (23%), and ovarian/fallopian tube cancer (17%), with the remaining 26% made up of various cancer types, including skin, breast, lung, brain, and other cancers. Results: Of the pan-tumor cohort, 95% of cases had at least one actionable protein target identified, compared to 86% of cases with clinically relevant genomic alterations. Altered genes and Theralink RPPA assay protein targets were broadly classified into 10 biological pathways. The pathway most frequently identified as actionable via Theralink’s RPPA assay was HER-family protein signaling (85% of cases) with concurrent genomic alterations in HER-family genes found for 9% of cases. In contrast, mTOR signaling was found to be the most frequent clinically relevant genomically altered pathway (48% of cases). When using a clinical breast cancer reference for HER2 protein/phosphorylation levels that is guiding HER2-targeted therapy in the unamplified setting, actionable total and phospho-HER2 levels were found in 82% of the pan-tumor cases, overlapping with ERBB2 genomic alterations in 4% of cases. The gene found to be altered the most was TP53 (101 cases; 54%), which was not part of the targeted Theralink RPPA assay. Conclusions: Our data suggest that quantification of key cancer proteins and phosphoproteins using RPPA extend the identification of actionable drug targets beyond what was found with WES/WTS testing alone. Especially the quantification of total and phospho-HER2 identified a significant pan-tumor subpopulation that may benefit from HER2-targeted therapies, including trastuzumab deruxtecan (T-Dxd).
Baseline endogenous serum testosterone levels and all-cause mortality in men with prostate cancer treated by radical radiotherapy: 11-year follow-up data.
Authors: Santhanam Sundar, Ewan Shawcroft, Lauren Jones, Micheal O'Cathail, Shaymaa Usama Hosni, Jessica Little, Georgina Walker, Ashley Cox, Eamonn Fergusson
Journal: Journal of Clinical Oncology (2023)

e17003 Background: Low levels of serum testosterone are associated with higher all-cause mortality and cardiovascular mortality in some studies.(PMID: 18040028). But men with low levels of serum testosterone at reduced risk of developing prostate cancer. (PMID: 30077399). In middle-aged and elderly men, single point testosterone measurements have been shown to reliably reflect long term androgen exposure. [PMID: 1548361]. We assessed the interaction of pre-treatment serum testosterone levels and long term all-cause mortality in men with newly diagnosed prostate cancer. Methods: Prostate cancer pts enrolled in an ethics approved, prospective study evaluating a rating scale. Baseline serum testosterone levels were measured before the pts were commenced on androgen deprivation therapy and radical radiotherapy. Patient characteristics: Mean age 68.2yrs (median 69yrs); Age range category &lt; 60yrs:14.9% , 61-70yrs:47.3% and &gt; 71 yrs: 37.8%. Charlson Comorbidity Index (CCI) prevalence at baseline as follows CCI- Low risk : 39.9%; CCI-medium risk : 51.4%; CCI-high risk: 8.8%. PSA median level was 10.85 ug/L. Tumour was localised in a majority of pts- stage T1/T2 in 72% . Pts with M1 disease were not enrolled. Histology grade: Gleeson grade 6 in 7.4% and Gleeson grade 7 in 53.4% . Serum testosterone: Median 11.9 nmol/l; Mean 12.4 (Min-Max 2.6 to 26.7). Cox proportional hazards regression used to analyze the effect of baseline Serum Testosterone on long term overall survival, while controlling for covariates (age, cancer T stage, PSA category, Gleeson Category and Charlson Comorbidity index). Results: Lower levels of serum testosterone at baseline were associated with decreased all-cause mortality. There was no significant correlation between testosterone levels and age in our study sample of relatively elderly population (Pearson Correlation p = 0.362); There was no correlation testosterone levels and PSA levels(P = 0.821); no association between serum Testosterone levels and Gleeson Grade as well as T stage. (F = 0.78 ; P = 0.46 and F = 1.34 ; P = 0.26 respectively). There was also no significant variation in testosterone levels according to Comorbidity categorised by Charlson Comorbidity Index. (F = 1.31 P = 0 .26). Conclusions: Lower Serum testosterone levels were associated with decreased all-cause mortality in this prospectively collected survival data of non-metastatic Prostate cancer patients. [Table: see text]
Penpulimab plus platinum-based chemotherapy combined with anlotinib in first-line treatment for persistent, recurrent, or metastatic cervical cancer: A single-arm, open-label phase Ⅱ study (ALTN-AK105-II-06).
Authors: Qin Xu, Jing Liu, Li Li, Yibin Lin, Ying Chen, Yanwen Song, Lan Luo
Journal: Journal of Clinical Oncology (2023)

e17512 Background: Penpulimab is a novel human immunoglobulin G1 (IgG1) anti-programmed cell death-1 (PD-1) antibody. Anlotinib is a novel oral multi-target tyrosine kinase inhibitor and primary targeted to VEGFR, FGFR, PDGFR and c-Kit. ALTN-AK105-II-06 (ChiCTR2200062897) is a single-arm, open phase Ⅱ clinical trial aimed to assess the effiacy and safety of penpulimab plus chemotherapy combined with anlotinib as fist-line therapy for persistent, recurrent, or metastatic cervical cancer. Methods: Eligible adults with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemotherapy and not amenable curative treatment, with CPS more than 1% PD-L1 expression, and ECOG 0-1 were considered eligible for enrolment. Patients received 2 cycles of penpulimab 200mg Q3W + chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) + anlotinib 10mg, following with penpulimab and anlotinib for maintenance therapy. Patients were treated on continuous 3 weeks of penpulimab for up to 2 years, until disease progression, or unacceptable toxicities. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DoR), overall survival (OS), 6-month PFS, safety and quality of life. Results: From Sep 2022 to Feb 2023, 9 patients were recruited with a median age of 56.4 years (range: 45-66), FIGO histopathological stage IIB (33.3%), III (44.5%) and IV (22.2%) were enrolled. 22.2% patients had ECOG PS 0. At data cutoff date (Feb 02, 2023), 8 patients had at least one post treatment anti-tumor assessment. 1 (12.5%) patient achieved CR, 6 (75%) patients achieved PR and 1 (12.5%) patient NE. The ORR was 87.5%. Median PFS and OS were not reached. Grade ≥3 TRAEs incidence was 44.44%. The most common grade ≥3 TRAEs were hypertension (22.22%), leukopenia (11.11%), neutropenia (11.11%) and hypertriglyceridemia (11.11%). Conclusions: This chemo-less therapy of only 2 cycles of chemotherapy combined with penpulimab + anlotinib in first-line treatment, maintaining with penpulimab and anlotinib showed promising efficacy with a favourable toxicity profile for patients with persistent, recurrent, or metastatic cervical cancer. We will report more data in the future. Clinical trial information: ChiCTR2200062897 .
Evaluation of immune related adverse events following extended interval dosing of immune checkpoint inhibitors.
Authors: Jake Anthony Deviley, Yacki Hayashi-Tanner, Susan M Frankki, David E. Marinier
Journal: Journal of Clinical Oncology (2023)

e14605 Background: Increased use of immune checkpoint inhibitors (ICI) has resulted in a rise in immune related adverse events (irAEs). In 2019, pembrolizumab and nivolumab received approval for extended interval (EI) dosing at 400 mg intravenous (IV) every 6 weeks and 480 mg IV every 4 weeks, respectively, compared to the standard interval (SI) dosing of 200 mg IV every 3 weeks and 240 mg IV every 2 weeks, respectively. Since EI dosing has been implemented, clinicians have hypothesized increased dosing may lead to more irAEs. Mixed results have been published to date with discordant results between studies. The aim of this study was to investigate the incidence and grade of irAEs, including multisystem adverse events (ms irAEs) in SI versus EI dosing in a real-world community-based hospital system in the United States of America. Methods: We performed an Institutional Review Board approved retrospective study of all patients 18 years or older who received SI or EI dosing of pembrolizumab or nivolumab from 2015 through 2021. An irAE was considered connected to the specific dosing group if it was observed after the first date of stated dosing and within 90 days after last dose of such dosing. Statistical analysis included descriptive statistics, Wilcoxon signed-rank test, Fisher’s exact test, and Kaplan-Meier survival analysis and was performed in R version 4.2.2 at a significance level of 0.05. Results: Our study included 458 patients who were 99% white, 59% male, and an average age of 67 years. There were 354 (77%) patients in the SI group and 104 (23%) in the EI group. The overall incidence of irAEs was 32% (146 patients), of which 37% (54 patients) presented at some point with ms irAEs. There was no significant association between dosing group and presence of irAEs (p = 0.087), grade groups 1-2 vs &gt; 3 (p = 0.7), or ms irAEs (p = 0.13). The incidence of irAEs was 34% (120 patients) in the SI group with a distribution of grades 1-2-3-4-5 being 39-62-25-5-1, respectively. The incidence of irAEs was 25% (26 patients) in the EI group with a distribution of grades 1-2-3-4-5 being 18-27-11-1-0, respectively. In the SI group there were 41 (34%) patients with ms irAEs compared to 13 (50%) in the EI group. There was a significant association between dosing groups and overall survival (p &lt; 0.001). Conclusions: Our results lend data to suggest there is indeed no statistically significant risk of increased irAEs with EI dosing. However, there may be a clinically significant trend toward increased ms irAEs in EI dosing that needs further investigation with comparisons of comorbid conditions that increase risk of autoimmune reactions. Of note, the OS in EI dosing group was statistically significant but likely heavily confounded due to patient selection bias, this may also be an avenue for future research to be conducted with a randomized clinical trial.
3D genomics identifies previously unreported yet clinically actionable gene fusions and complex rearrangements in a cohort of driver-negative colorectal carcinoma tumors.
Authors: Kristin Sikkink, Alyssa Beck, Anthony Schmitt, Darren Sigal
Journal: Journal of Clinical Oncology (2023)

e15608 Background: Molecular characterization by next-generation sequencing (NGS) has been unable to detect pathogenic driver mutations in a significant number of tumors. For example, 40% of colorectal carcinomas (CRC) are RAS and BRAF wild-type and do not have therapeutic targets after comprehensive molecular characterization using FISH, IHC and NGS. Analysis of 3D genomics data produced by DNA-based chromosome conformation capture (Hi-C) assay has been shown to detect gene fusions and other rearrangements in tumor biopsies. We applied Hi-C in a cohort of CRC tumors previously characterized using FISH, IHC, whole exome sequencing (WES) and whole transcriptome sequencing (WTS) by a large commercial reference laboratory, where no targets had been reported, to evaluate the potential for Hi-C to identify novel therapeutic targets. Methods: FFPE tissue from 14 CRC tumors were subjected to Hi-C using the Arima HiC+ for FFPE kit. Hi-C libraries were sequencing to ~100M raw read-pairs on an Illumina NovaSeq, and fusions were called using the Arima-SV pipeline. To attribute clinical significance, we characterized fusions based on whether the fusion event involved a Tier 1 therapeutic level biomarker or a Tier 3 diagnostic or prognostic biomarker according to NCCN and OncoKb, or a Tier 2 biomarker if the biomarker was the target of a therapy in an ongoing clinical trial. Results: Hi-C detected fusions implicating a Tier 1 biomarker in 50% (7/14) of tumors, a Tier 2 level biomarker in 14% (2/14), and a Tier 3 level biomarker in 14% (2/14). Homologous recombination repair (HRR) gene rearrangements were detected in 29% (n = 4/14) of CRC tumors, disrupting HRR genes ( BRIP1, BRCA1, BRCA2, RAD51D). NRG1 gene fusions were detected in 14% (2/14), and amplified complex rearrangement carrying KRAS was detected in one CRC case. A complex rearrangement involving extrachromosomal DNA (ecDNA) amplification carrying EGFR was detected in two cases that were both previously found to have EGFR amplifications, but the ecDNA nature was not previously known and was confirmed by FISH. Lastly, Hi-C detected gene rearrangements involving POLE or APC in two CRC cases, alterations in which are known to increase risk for colonic polyposis. Conclusions: Fusion detection by Hi-C in CRC may uncover numerous therapeutic biomarkers not currently detected by molecular profiling. Our data suggests that homologous recombination deficiency (HRD) may frequently result from HRR gene rearrangements readily detectable by Hi-C, and this alternate mechanism for HRD may serve as a therapeutic biomarker for HRD directed therapies. Our data also suggests that therapeutically targetable gene fusions and complex rearrangements involving therapeutic level biomarkers are also readily detectable by Hi-C, detection of which may increase the number of CRC patients treatable with targeted therapies.
Treatment with lenvatinib plus pembrolizumab in recurrent or advanced endometrial cancer: A systematic review and meta-analysis.
Authors: Francisco Cezar A Moraes, Maysa Vilbert, Sarah Vitoria B Carnevalli, Gustavo de Oliveira Almeida, Danielle Feio, Carlos Stecca, Alexandre Andre B. A. Da Costa
Journal: Journal of Clinical Oncology (2023)

e17630 Background: Endometrial cancer (EC) is the second most prevalent gynecological cancer. After failure to first-line platinum-based chemotherapy, treatment options are sparse, but recent studies have investigated new approaches with promising results. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Lenvatinib plus Pembrolizumab in patients with advanced or recurrent EC. Methods: PubMed, Web of Science, Cochrane, Scopus, and LILACS databases, Central Register of Clinical Trials, and congresses publication websites were searched for studies using Lenvatinib plus Pembrolizumab in advanced or recurrent EC with progression after platinum-based chemotherapy. Outcomes of interest were best overall response rate (BORR) and disease control rate (DCR), on intention-to-treat (ITT) and per-protocol analyses, and according to mismatch repair status. Progression free-survival (PFS) and overall survival (OS) were also assessed. Heterogeneity was examined with the Cochran Q test and I 2 statistics. We use a DerSimonian and Laird random-effects model. Results: Four studies, with 637 patients, were included: two clinical trials and two retrospective observational cohorts. Endometrioid EC was the predominant histology (53%), and most patients had mismatch repair-proficient tumors (pMMR, 86.5%). In a pooled analysis, with a medium follow-up of 12.2 months, BORR was 31% (95%CI 26, 37), and DCR was 74% (95%CI 65, 83) on ITT. CR, PR, and SD were documented in 37 (5.8%),168 (26.3%) and 284 (44.5%) patients, respectively. BORR was 48% in microsatellite unstable tumors compared to 31% in stable microsatellite disease (p = 0.07), while DCR was similar in both groups (p = 0.33). Median progression-free survival was 7.2 months (95%CI 3.2, 7.4), and median overall survival was 18.3 months (95%CI 8.6, 18.3) in patients receiving Lenvatinib and Pembrolizumab. The most common treatment-related adverse events (AE) included diarrhea 277/514 (53.8%), nausea 244/514 (47.4%), hypothyroidism 288/562 (39.1%), hypertension 338/632 (36.9%), fatigue 213/632 (31.0%), and vomiting 178/514 (34.6%). Grades 3 or 4 AE was reported in 436/514 (79.6%) patients. Overall, dose reductions, treatment interruptions, and discontinuation due to toxicities were required in 61%, 63%, and 27% of patients, respectively. Conclusions: This systematic review and meta-analysis reinforce the antitumor activity of the combination of Pembrolizumab and Lenvatinib in patients with advanced or recurrent EC, regardless of MMR status. Despite high rates of serious adverse events related to treatment, most were manageable.
A retrospective study on the efficacy and safety of regorafenib alone or in combination in advanced hepatocellular carcinoma.
Authors: Shouzhong Fu, Cong Chen, Suming Zhao, Feng Dai, Hongxin Yuan, Weiwei Gu, Zhuxin Gu, Rongfeng Shi, Pengfei Jia, Xiaohua Lu, Kang Chen, Ning He, Hui Zhao
Journal: Journal of Clinical Oncology (2023)

e16176 Background: The earlier randomized phase III RESORCE trial and several real-world studies demonstrate that regorafenib improves overall survival (OS) in advanced hepatocellular carcinoma (HCC). This study aims to evaluate the efficacy and safety of regorafenib alone or in combinations in advanced HCC. Methods: 60 Patients with pathologically or clinically diagnosed advanced HCC were enrolled. We retrospectively analyzed the efficacy and safety of patients who received at least one cycle of regorafenib between March 7, 2019 and December 25, 2022 in the Affiliated Hospital of Nantong University and Nantong Third People's Hospital. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). The secondary endpoints were overall survival (OS), disease control rate (DCR), and safety. The safety and efficacy were assessed by investigators per CTCAE v5.0 and mRECIST v1.1, respectively. Data on survival rates were calculated using the Kaplan-Meier method. Results: The average age was 62.63 years, and 95% were male. Most patients had a Child-Pugh A score (73.3%), and the proportion of patients with BCLC stage B and C classes were 41.7% and 58.3%, respectively. 3 (5%) patients received single-drug regorafenib therapy, and the remaining patients (95%) received different combination therapies, including regorafenib plus immune checkpoint inhibitors (ICIs) (10%), regorafenib combined with TACE (40%), and triple therapy (TKI, ICI, TACE) (45%). The ORR and DCR were 40% and 92%, respectively. With a median follow-up of 16.10 months (95%CI, 11.067-21.133), the median PFS was 8.4 months (95% CI, 5.597-11.203), and the median OS has not been reached. Most patients tolerated 120mg or 160mg once daily during weeks 1–3 of each 4-week cycle. 23 patients (38.33%) experienced adverse events (AEs). The most frequent AE (≥5%) included hand-foot syndrome (23.33%), diarrhea (11.67%), and fatigue (6.77%). The incidence of grade 3 AE was 3%. No grade 4 AE and new safety signals were identified. Conclusions: Regorafenib alone or in combination had a manageable safety profile and promising efficacy in advanced HCC patients.
Donafenib combined with anti-PD-1 antibodies plus transarterial therapy for initially unresectable hepatocellular carcinoma.
Authors: Yaohong Wen, Shunjun Fu, Guolin He, Lei Cai, Yahong Liu, Xinmin Li, Yuyan Xu, Chunming Wang, Kaihang Zhong, Cheng Zhang, Qingyu Xie, Mingxin Pan
Journal: Journal of Clinical Oncology (2023)

e16135 Background: Given its clear efficacy and high safety demonstrated in the phase 3 ZGDH3 study, donafenib has been recommended by the Chinese guidelines for the first-line treatment of unresectable hepatocellular carcinoma (uHCC). Recently, combination therapies have shown favorable results. However, triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy has not yet been investigated. Thus, we aimed to investigate the efficacy and safety of triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy in patients with uHCC. Methods: A single-center, retrospective study was performed based on the medical records of consecutive patients diagnosed with HCC who were not suitable for curative surgery or local ablation at Zhujiang Hospital of Southern Medical University from June 2021 to October 2022. Patients with ≥18 years, Child-Pugh score ≤7, ECOG PS ≤1, no prior systemic therapy, having at least one measurable lesion (per mRECIST) were enrolled. Patients were treated with donafenib 200 mg orally twice daily, anti-PD-1 antibodies intravenously every three weeks, and transarterial therapy until disease progression or unacceptable toxicity. Endpoints include objective response rate (ORR, the proportion of patients with partial or complete response according to mRECIST and RECIST v1.1), surgical conversion rate (the proportion of patients who successfully underwent resection), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: A total of 27 patients were enrolled (median age 52 years [range, 29–74], 81% males, 85% with HBV infection, 41% with cirrhosis, 48% with AFP level ≥400 ng/mL, and 67% in BCLC C). All patients received donafenib and anti-PD-1 antibodies with hepatic arterial infusion chemotherapy (HAIC, n = 10), transarterial chemoembolization (TACE, n = 8), or both (n = 9). By the cutoff date of January 6, 2023, the median follow-up duration was 6.8 months (95% confidence interval [CI], 5.9–7.7), and 17 (63.0%) patients were still undergoing treatment. The ORR and DCR were 59.3% and 92.6% by mRECIST, and 18.5% and 88.9% by RECIST v1.1, respectively. The surgical conversion rate was 22.2%, and the median surgical conversion time was 3.4 months (range, 2.2–4.6). The median PFS was 8.3 months (95% CI, 6.8–9.8), and median OS was not reached. The 6-month PFS rate and 12-month OS rate were 74.7% and 72.9%, respectively. Grade 3 treatment-related adverse events (TRAEs) were observed in 5 patients (18.5%), the most common of which was increased total bilirubin (11.1%). No grade 4/5 TRAEs occurred. Conclusions: Donafenib combined with anti-PD-1 antibodies plus transarterial therapy shows promising efficacy and manageable toxicity in patients with initially uHCC. Clinical trial information: NCT05638438 .